The relatively high incidence of human neonatal morbidity and mortality associated with low birth weight and prematurity require that there be a more intensive study of the mechanisms underlying placental and fetal development. Our present understanding of the factors regulating growth and morphological and functional maturation of the placenta in preparation for development of the fetus, is incomplete. The overall objective of the present proposal is to improve knowledge in this area by building on our previous in vivo studies in the pregnant baboon demonstrating that the placenta is an estrogen target tissue. Study I will test the hypothesis that estrogen regulates proliferation of mononucleated villous cytotrophoblasts and/or their morphological differentiation into syncytiotrophoblasts. The goals of Studies I and II are interwoven to test the hypothesis that as a result of estrogen- regulated morphological and functional differentiation of trophoblasts, the Il (3-hydroxysteroid dehydrogenase (1 1I3-HSD)- 1 and -2 enzymes, that catalyze cortisol (F) and cortisone (E) interconversion, undergo spatial orientation within the syncytiotrophoblast resulting in transplacental oxidation of bioactive F to bioinactive E, and thus derepression of F feedback on and maturation of the fetal hypothalamic-pituitary- adrenocortical axis (HPAA). Studies II and III are integrated to test the hypothesis that estrogen has two different effects on the fetal HPAA: an indirect one to enhance, via placental II beta- HSD, fetal pituitary ACTH release and thus maturation of the fetal adrenal definitive zone with de novo production of F critical to fetal lung maturation, and a direct negative action on the fetal zone to modulate ACTH receptor-mediated C19-steroid synthesis to ensure an appropriate level of estrogen production. In vivo physiological measurements of placental, fetal adrenal and lung function coupled with histo/anatomical, biochemical, and molecular parameters of trophoblast differentiation and fetal organ system development will be determined in baboons in which estrogen levels are prematurely elevated or suppressed by a highly specific aromatase inhibitor during gestation. The estrogen- depleted/-repleted pregnant baboon provides a novel and unique model to investigate the effects of altered trophoblast differentiation on maturation of fetal organ systems essential to neonatal survival, studies which could not be performed in pregnant women. The results derived from the proposed study will provide new insight into the communication that occurs between the fetus and placenta and ultimately improve our knowledge of the regulation of pregnancy maintenance and development of neonatal self-sufficiency.